We are examining the major depression (MDD) that occurs during exposure to elevated levels of inflammatory cytokines, and specifically focusing on the MDD that develops during interferon-alpha (IFN-a) therapy (IFN-MDD). Because hepatitis C is very prevalent and the primary treatment is IFN-a-based, IFN-MDD is a common disorder. Because IFN-MDD develops within the few months of IFN-a treatment, it is a tractable condition for prospective study, and may be a good target for preventive intervention if those most vulnerable can be identified. A potential advantage is that a homologous set of behaviors can also be induced in IFN-treated mice. Our preliminary studies (i) support a growing literature that IFN-MDD shares many homologies with other MDD types and (ii) find that the whole genome transcriptome from mononuclear cells may be able to predict who is vulnerable to developing IFN-MDD and who is not. These results have identified the mitogen-associated protein kinase (MAPK) pathway as potentially being associated with this vulnerability. The next step that we propose is to determine mRNA biomarkers for IFN-MDD -- using Affymetrix microarrays to prospectively examine mRNA transcriptomes in humans receiving IFN-a-based therapy. In concert, we also intend to develop an animal platform as a translational approach for verifying molecular biomarker transcription patterns - of potential value for causally testing some of the biomarker pathways found in human IFN-MDD. For this, we propose to examine the mRNA transcriptomes and behaviors of mice treated with a behaviorally active human-mouse consensus IFN-a. The data generated by this 2-year study will guide our systematic next steps, which includes a more targeted and statistically powered investigation of the micro-array-identified pathways.